Epilepsy is a common chronic neurologic disorder which causes recurrent seizures and affects 0.5 to 1 percent of the population (Hauser et al., EPILEPSIA 34:453 (1993)). Seizures occur when there is an imbalance in the electrical activity of the brain. The abnormality may be in a small area of the brain or may involve the entire brain. Epilepsy can be congenital or can also be caused by head injury, birth trauma, infections, brain tumor, hemorrhage, or stroke. Diagnosis of epilepsy requires multi-modality testing, often in multiple phases. Initially, clinical exam and patient history are of primary importance for diagnosis. Other tests may include magnetic resonance imaging (MRI) to examine for structural abnormalities, single photon emission computed tomography (SPECT or positron emission tomography (PET) to examine for functional abnormality, electroencephalography (EEG) to record electrical impulses of the brain and their foci, magnetoencephalography (MEG) to co-localize electrical foci with structural abnormalities, and blood tests to exclude other diseases.
In spite of optimal medical management, more than one-third of all epilepsy patients have incompletely controlled seizures or debilitating medication side effects (Kwan and Brodie, N. ENGL. J. MED. 342:314 (2000); Sander, EPILEPSIA 34:1007 (1993); Sillanpaa and Schmidt, EPILEPSY BEHAV. 8:713 (2006)). Medically refractory epilepsy is associated with excess injury and mortality, psychosocial dysfunction, and significant cognitive impairment. Resective or disconnective surgery is associated with long term seizure freedom in 60-80% of patients (Engel, Jr. et al., EPILEPSIA 44:741 (2003); Engel, Jr. et al., NEUROL. 60:538 (2003); Lee et al., ANN. NEUROL. 58:525 (2005)). Surgery for patients whose epilepsy has proven refractory to anti-epileptic drugs (AEDs) provides a high likelihood, of reduction in seizure frequency, is generally safe, and is recommended for selected patients with refractory partial seizures.
In order to appropriately diagnose epilepsy for possible surgical intervention, it is generally necessary to conduct an inpatient workup, referred to as Phase I monitoring. The primary goal of this analysis is to confirm the diagnosis of epilepsy and requires simultaneous video and electroencephalographic (EEG) monitoring, 24 hours a day in an epilepsy monitoring unit (EMU), which enables correlation of complete clinical behavior, with seizure information from the EEG. Through Phase I monitoring, the part of the brain responsible for seizure activity can often be localized. However, if data collected during the Phase I admission does not provide enough information to localize the seizure focus, then invasive, inpatient, Phase II monitoring may be needed. This standard approach involves surgery to place cortical electrodes and depth electrodes directly into the brain. Cortical electrodes consist of parallel rows of electrode contacts placed directly on the cortical surface of the brain. Depth electrodes are inserted into the brain to reach deep recording sites, often in the hippocampus and amygdala. These electrodes are placed to provide more accurate information as to the location of epileptic focus and to correlate with continuous video monitoring. After recovery from surgery, implanted electrodes are connected to monitoring equipment which can detect seizure activity and localize seizure foci. In order to provoke seizures, anti-epileptic medications are often weaned or discontinued.
The Hippocampus in Seizure Generation
Mesial temporal lobe epilepsy (MTLE) is a common form of medically-refractory epilepsy which is characterized by spontaneous and progressive seizures. Mesial structures include the amygdala, the uncus, the hippocampus, and the parahippocampal gyrus. While in many patients it can be associated with past hippocampal injury followed by a latency period of 5-10 years, other cases are idiopathic. Characteristic changes are well described in the hippocampus of MTLE patients, including structural changes of sclerosis and gliosis, predictable neuronal loss in particular hippocampal subfields and molecular changes leading to hyperexcitability, as recently reviewed (O'Dell et al., J. NEUROSCI. RES. 90:913 (2012)). Diagnosis of MTLE conventionally requires the multi-modal approach described above to define the hippocampus as a seizure generator. The depth electrodes conventionally placed are composed of a series of macrocontact electrodes which are designed to detect a narrow frequency bandwidth (0.1-100 Hz) of neuronal field potential changes from a large surface area of the brain with a wide inter-electrode spacing (5-10 mm apart) (Worrell et al., BRAIN 131:928 (2008)).
The Use of High Frequency Oscillations and Spatiotemporal Correlation for the Detection of Seizures
While the conventional, slow frequency range is useful for the detection of seizures, it neglects higher frequency ranges and more specific, single neurons which are likely useful in the early detection of seizure activity (Truccolo et al., NATURE NEUROSCI. 14:635 (2011)). High-frequency oscillations (HFO) have been described including ranges of 80-250 Hz, >250-500 Hz (Bragin et al., J. NEUROSCI. 22:2012 (2002); Bragin et al., ANN. NEUROL. 52:407 (2002); Worrell et al., BRAIN 131:928 (2008)) and even higher (up to 10 K Hz) (Bower et al., 2012). Higher frequency oscillations are thought to be unique to the pathologic hippocampus as they have been identified primarily in the epileptic kainate rodent model (Bragin et al., EPILEPSIA 40:127 (1999)) and the epileptic human mesial temporal lobe (Bragin et al., EPILEPSIA 40:127 (1999); Bragin et al., ANN. NEUROL. 52:407 (2002)). Reliable detection of these HFOs are optimized from implanted microelectrodes using supra-standard filtration (Bower et al., EPILEPSIA 53:807 (2012); William, J. NEURONAL ENG. 9:056007 (2012); Worrell et al., BRAIN 133:928 (2008)). Simultaneous recording from macro/micro electrodes indicate that HFOs are increased in seizure generating zones of the human mesial temporal lobe prior to or at the onset of seizures, and that the presence of these electrographic signals may be more sensitive than structural changes typically relied upon for hippocampal involvement in seizure generation (Worrell et al., BRAIN 131:928 (2008)). Supporting these findings, a cat model of seizures shows that ripple-frequency HFOs are strongly associated with seizure onset, and evidence suggests that they may play a fundamental role in recruiting surrounding neuronal tissue into seizing, thus creating a. pathological summation effect of seizure propagation (Grenier et al., J. NEUROPHYSIOL. 86:1884 (2001)).
Hippocampal Subfield Anatomy
In brief, the anatomical hippocampus is subdivided into subfields known as the CA1-CA4 regions, each populated by a stereotypical cytoarchitecture with predictable synaptic interconnections between subfields (DUVERNOY, THE HUMAN HIPPOCAMPUS: FUNCTIONAL ANATOMY, VASCULARIZATION AND SERIAL SECTIONS WITH MRI (2005)). Importantly, the subfield of CA3 gives putative monosynaptic input to the CA1 subfield via a collection of pyramidal neuronal axons known as the Schaffer collateral system (Schaffer, ARCH. MIKROSKOP. ANATOMIE 39:611 (1892)); the CA1 subfield subsequently serves in the main output pathway of the hippocampal formation. In the past several years, much attention has focused on how the firing pattern of CA3 neuronal population influences the neuronal discharge of the CA1 subfield (Guzowski et al., NEURON 44:581 (2004)) leading recently to the development of verified animal models which reliably predict multineuronal ensemble firing patterns of CA1 based on the recorded discharge patterns of CA3 (Berger et al., J. NEURONAL ENG. 8:046017 (2011); Hampson et al., IEEE TRANSACTIONS 20:184 (2012)).
Recording of these hippocampal ensembles for use in functional predictions of seizures can now be readily adapted to human application using FDA-approved materials within a well-defined clinical application.
Hippocampal Recording and Development of Neuronal Ensemble Models from Animal Studies
As described above, the hippocampus has a stereotypical cytoarchitecture which includes a putative monosynaptic connection between subfields (DUVERNOY, THE HUMAN HIPPOCAMPUS: FUNCTIONAL ANATOMY, VASCULARIZATION AND SERIAL SECTIONS WITH MRI (2005)). The neuronal output of CA3 has recently been shown in mathematical models of animal hippocampus to influence the neuronal activity pattern of CA1 neurons, forming a neuronal ensemble. In the rodent hippocampus, one such operational nonlinear systems model characterized the neuronal activity of CA1 utilizing individualized or generic inputs derived from CA3 neurons, recorded while the animals underwent cognitive behavioral testing (Berger et al., J. NEURONAL ENG. 8:046017 (2011); Hampson et al., IEEE TRANSACTIONS 20:184 (2012); Zanos et al., IEEE TRANSACTIONS 16:336 (2008)). Development of this model has been shown to allow reliable recording of CA3 neuronal discharges with subsequent accurate prediction of the activity or CA1 postsynaptic cells via the Schaffer collateral system (Berger et al., J. NEURONAL ENG. 8:046017 (2011)).